Glaucoma is a leading cause of blindness in the United States, and the second leading cause worldwide. There is consensus that the level of IOP generates a biomechanical response in the ocular tissues that is fundamental to the early events in glaucoma damage. The IOP is translated into mechanical stresses on the optic nerve head, an opening in the posterior sclera for the passage of retinal ganglion cells (RGC) to the brain, by the response of the posterior sclera. This causes deformation of the RGC axons, glia, and nourishing capillaries. At the optic nerve head, it is well established that blockade of axonal transport in RGC axons leads to their ultimate death. Thus, the physical interaction of the sclera at the optic nerve head is central to the development of glaucomatous optic neuropathy. Improved knowledge of the mechanical behavior of these structures will advance understanding of glaucoma injury, its early diagnosis, and prevention of the blindness caused by the disorder. The goals of the proposal are to (1) measure the regionally varying thickness, anisotropy of the collagen and elastin structure, the inflation response to IOP fluctuations, and viscoelastic properties of the posterior human sclera, comparing for the effects of age, sex, severity of glaucoma damage, and effects of various enzymatic and collagen cross linking agents, and (2) model the effects of the measured variations in scleral viscoelastic properties and structure on the response of the ONH to dynamic fluctuations in IOP. It is likely that the viscoelastic properties and structure of human eyes with open angle glaucoma differ from those of normal eyes. These are in turn likely altered by the progression of glaucoma damage. Differences between glaucoma and normal eyes in their physiological or anatomical features will suggest candidate genes for improved diagnostic testing, as well as post-translational processes and pathways that would be amenable to new therapeutic approaches. We will begin to explore the development of therapeutic approaches that alter the viscoelastic behavior of the sclera by collagen cross linking to stiffen the sclera and enzymatic degradation of soften the sclera. PUBLIC HEALTH RELEVANCE: Glaucoma is a leading cause of blindness in the United States, and the second leading cause worldwide. The implications of this work can be important to understanding the susceptibility of individuals to glaucoma. We can envision the development of non-invasive testing procedures, that for example measure a key mechanical property of the sclera, to identify individuals at risk and determine their degree of susceptibility based on the biomechanical properties of their eyes.